The current proposal is a competitive revision to the Program Project (2P01NS045685-06A1-PI Dr Maixner) in which we propose to explore the role of mitochondrial inheritance as a shared pathway for co-morbid Complex Persistent Pain (CPP) conditions. Our group has recent data suggesting that certain mitochondrial DNA (mtDNA) polymorphisms are associated with several CPP, including migraine and IBS, suggesting that impaired energy metabolism may be a shared pathway. In this revision we will explore the relationship between polymorphic changes in the entire mtDNA to identify candidate polymorphisms associated with CPP. This is a novel pathway to be explored in CPP and fits seamlessly into the goals of the Program Project. Exploring mtDNA, in addition to nuclear DNA, psychological and physiological factors as already proposed in this program project grant, would enhance our understanding of the shared risk factors for complex persistent pain disorders. To this end, existing blood samples obtained in the project grant will be used for genetic analyses, supplemented with banked samples. In a subgroup (N=400) of patients and controls, we will cyclosequence the entire mtDNA. Any polymorphism demonstrating a potential trend association with CPP, will be studied by PCR-RFLP in the whole sample (N=1850). In addition, detailed pedigrees will be obtained to determine the presence and degree of a maternal inheritance pattern of functional symptoms/disorders and association with identified polymorphisms. Data collected on mtDNA will be integrated with nuclear genetic data for analysis and modeling within the original aims of the PPG. Identification of disease-associated mtDNA sequence variants could provide mechanistic insight and clinical advances, and establish a new pathogenic model for understanding mtDNA-mediated polygenic susceptibility in CPP.